Insights into the κ-P,N Coordination of 1,3,5-Triaza-7-phosphaadamantane and Derivatives: κ-P,N-Heterometallic Complexes and a 15N Nuclear Magnetic Resonance Survey

Complexes {[(PTA)2CpRu-μ-CN-1κC:2κ2N-RuCp(PTA)2-ZnCl3]}·2DMSO (13) {[ZnCl2(H2O)]-(PTA-1κP:2κ2N)(PTA)CpRu-μ-CN-1κC:2κ2N-RuCp(PTA)(PTA-1κP:2κ2N)-[ZnCl2(H2O)]}Cl (14), [RuCp(HdmoPTA)(PPh3)(PTA)](CF3SO3)2 (20), [RuCp(HdmoPTA)(HPTA)(PPh3)](CF3SO3)3 (21), and [RuCp(dmoPTA)(PPh3)(PTA)](CF3SO3) (22) were obtained and characterized, and their crystal structure together with that of the previously published complex 18 is reported. The behavior of the 1,3,5-triaza-7-phosphatricyclo[3.3.1.13,7]decane (PTA) and 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (dmoPTA) ligands against protonation and κN-coordination is discussed, on the basis of 15N nuclear magnetic resonance data collected on 22 different compounds, including PTA (1), HdmoPTA (7H), and some common derivatives as free ligands (2–6 and 8), along with mono- and polymetallic complexes containing PTA and/or HdmoPTA (9–22). 15N detection via 1H–15N heteronuclear multiple bond correlation allowed the construction of a small library of 15N chemical shifts that shed light on important features regarding κN-coordination in PTA and its derivatives.


■ INTRODUCTION
Today, hydrophilic phosphines are very common ligands in organometallic and coordination chemistry. 1,2 In this class of compounds, monodentate m-monosulfonated PPh 3 (m-TPPMS) and tris-m-sulfonated PPh 3 (m-TPPTS) are among the most popular examples, but bidentate diphosphines and tridentate tripodal phosphines are also known and have been used. 3 There are also examples of hydrosoluble cage-like phosphines such as Verkade-type phospha-amides 4 and 1,3,5triaza-7-phosphaadamantane (1), which was first reported in 1974 by Daigle et al. (usually abbreviated as PTA or pta; the acronym TPA and the name "monophosphaurotropine" have been also used to indicate the ligand; the IUPAC name is rarely used in the scientific literature). 5 This ligand contains a soft phosphorus atom and three hard nitrogen atoms, which can be functionalized providing a large variety of derivatives (some examples are shown in Figure 1), 6 useful for obtaining catalysts, 7−13 bioactive agents, 14−25 luminescent compounds, 26,27 and new materials. 28−35 During the past several years, we have devoted a great deal of effort to synthesizing mono-and polymetallic complexes containing PTA and its derivatives, affording good homogeneous catalysts for the isomerization of allylic alcohols in water 36−42 like complex 9, 43 highly antiproliferative compounds 44−47 such as compounds 17−19, 48,49 and hetero-metallic polymers like 15 built via assembly of dimetallic complex 12 through metallic moieties ( Figure 2). 50 The simplest functionalizations of the PTA cage are mono-and bis-N-methylation to afford the cationic ligands N-methyl-PTA (mPTA) (5) and N,N′-dimethyl-1,3,5-triaza-7-phosphaadamantane (dmPTA) (6). 46 While the first is very stable, the latter decomposes under mild conditions, providing the ligand 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (dmoPTA) (7). Half-sandwich Ru(II) complexes containing 7 and the protonated ligand 3,7-H-3,7-dimethyl-1,3,7-triaza-5phosphabicyclo[3.3.1]nonane (HdmoPTA) (7H + ), such as 17 and 18 (Figure 2), exhibit great antiproliferative activities 48 and the ability to chelate a second metallic moiety through the methylated nitrogen atoms. It was shown that the chelation of a second metal, such as in the bimetallic complexes [RuCp(PPh 3 ) 2 -μ-dmoPTA-1κP:2κ 2 N,N′-ZnCl 2 ](CF 3 SO 3 ) (19) and [RuCp(PPh 3 ) 2 -μ-dmoPTA-1κP:2κ 2 N,N′-CoCl 2 ]-(CF 3 SO 3 ), improved the antiproliferative activity that was found to be 200 times higher than that of cisplatin for T-47D and WiDr human solid tumor cell lines. 47,49 Most of the time, the coordination of PTA and its derivatives to one metal through the phosphorus atom can be proven by 31 P nuclear magnetic resonance (NMR). Nevertheless, spectroscopic characterization of κN-coordination by infrared (IR), Raman, ultraviolet−visible (UV−vis), and 1 H and 13 C NMR is not straightforward, and only singlecrystal X-ray diffraction can provide the needed confirmation, 51−54 which only ensures the N coordination only in the solid state. Thus, to obtain more information about whether and how PTA and its derivatives are coordinated by the N atoms, we thought to lean on nitrogen NMR.
The most abundant isotope of nitrogen, 14 N, is quadrupolar; thus, most of the time, its detection is not practical. On the contrary, 15 N has a spin of 1 / 2 but its natural abundance is only 0.365%; therefore, the duration for data collection for nonenriched samples is usually very long. Nevertheless, this issue can be bypassed by the detection of 1 N via 1 H through longrange correlation experiments, today run by using routine and robust pulse sequences as heteronuclear multiple-bond correlation (HMBC) or heteronuclear multiple quantum correlation. 55 It is well established that 1 H− 15 N HMBC is a very useful tool for the structural assignments in protein sequences 56 and was also used for the characterization of natural products 57−61 and the structural resolution of isomers. 62 Also, various studies were published, including 15 N-enriched coordination compounds such as bimetallic clusters, 63 and in recent years, organometallic complexes

Scheme 1. Synthesis of 13 and 14
Inorganic Chemistry pubs.acs.org/IC Article were also characterized by this technique. 64−76 In this work, we used the 1 H− 15 N HMBC pulse sequence to investigate in solution some noncoordinated PTA derivatives ( Figure 1) as well as some previously published representative Ru halfsandwich complexes displaying κPand κP,Ncoordination ( Figure 2). Additionally, the new monometallic (20−22) and polymetallic (13 and 14) complexes containing dmoPTA and/ or PTA were synthesized and characterized by single-crystal Xray diffraction, expanding the family of PTA-κP,N-complexes, illuminating new aspects of the coordination behavior of the PTA and dmoPTA ligand in the solid state and solution.

■ EXPERIMENTAL PROCEDURES
Synthesis and Characterization of 13 and 14. Trying to obtain an analogue of polymer 15 with Zn instead of Cd, we reacted bimetallic complex 12 with 3 equiv of ZnCl 2 in water. Immediately, a light brown precipitated formed, which was redissolved in dimethyl sulfoxide (DMSO) and water. When the DMSO solution is cooled, complex [(PTA) 2 CpRu-μ-CN-1κC:2κ 2 N-RuCp(PTA) 2 -ZnCl 3 ] (13) crystallizes as the DMSO solvate, while upon evaporation of the water solution, (14) was obtained (Scheme 1). Structures of these complexes were characterized by single-crystal X-ray diffraction, as described below, but the first assessment of their different composition was first allowed by comparison of their IR spectra. The cyanide vibration frequency is significantly different for 13 (2131 cm −1 ) and 14 (2109 cm −1 ), and the IR spectrum of 14 shows H 2 O stretching and bending bands (3479 and 1623 cm −1 , respectively), which are absent in 13.
The 31 P{ 1 H} NMR spectra in D 2 O of both complexes 13 and 14 display two singlets in a 1:1 ratio, at −19.8 and −22.4 ppm, respectively. This behavior agrees with the cleavage of the PTA-Zn bond upon dissolution, as previously reported for other PTA-k-P,N complexes. 50,77,78 Synthesis and Characterization of 20 48 Crystal Structure of 13 and 14. Complexes 13 and 14 crystallize in the P 21 /n and P1̅ space groups, respectively. Selected bond lengths and angles are listed in Table 1, while a complete list can be found in Tables S7, S8, S12, and S13. In  77,78,85 With regard to the intermolecular contacts, in the crystal packing of 13, there is no interaction worth mentioning, while in 14, each tetrametallic moiety of 14 is connected to four neighboring complexes via the O1 and N6 atoms, forming hydrogen-bonded layers along the reciprocal b*−c* plane ( Figure 4).   Tables S7, S8, S12, and S13. Anions, solvent molecules, and hydrogen atoms connected to the carbon atoms have been omitted for the sake of clarity.
were obtained by slow evaporation of a solution of the corresponding complex in water and methanol, respectively. Selected bond distances and angles for the three complexes are listed in Table 2, and complete lists of bond lengths and angles are provided in Tables S9−S11 and S14−S16. The asymmetric unit of complex 18·CHCl 3 contains a [RuCp(PPh 3 ) 2 (dmoPTA-κP)] + molecule, one CF 3 SO 3 − , and one CHCl 3 . The coordination sphere of the ruthenium atom displays a pianostool geometry and is constituted by a η 5 -Cp, two PPh 3 ligands, and one dmoPTA ligand ( Figure 5). Bond distances between the metal and the Cp centroid and phosphine P atoms are similar to those found for similar complexes (Table 2) Table 2, which also includes the data of 17 48 for the sake of comparison (structure not shown). Anions, solvent molecules, and hydrogen atoms connected to carbons have been omitted for the sake of clarity.  (4) Å, which is like that found in 18. The protonation of PTA in 21 is localized on the N4 atom, which is part of a network of hydrogen bonds with water molecules and triflate anions ( Figure 6).
It is important to additionally consider the effect of the deprotonation of the HdmoPTA ligand in complexes 18 and 22. When the CH 3 N dmoPTA atoms are not H-bridged, the bottom rim of the triazaphosphaadamantane-like cage opens through an inversion about one of the methylated nitrogen atoms, which moves away from their lone pairs from each other. Given that in 18 and 22 the molecules are not connected by a network of hydrogen bonds, the greater N1− N2 length in 18 and 22 may suggest that their distance is susceptible to the steric hindrance of the surrounding ligands, which in 18 imposes a larger separation between the methyl groups ( Figure 7). Intending to predict the N′−N″ chelation behavior of the dmoPTA ligand, we find these data shed light on the possibility of chelating also metals with a van der Waals radius larger than those of Zn, Ni, and Co, which are the only examples of dmoPTA-κN′,N″-coordinated metals obtained to date. 89 Figure  1. Considering that selected metal-free triazaphosphines 1−3 display C 3v symmetry, while for ligands 4−8 is C S , in the first group only the cross peak due to three magnetically equivalent nitrogen atoms is expected, while for the second, two different signals should be found; the respective nitrogen atoms are numbered according to Figure 8. The obtained δ 15 N values for compounds 1−8 are summarized in Figure 8 and Table S1. As expected, only a 15 N signal was observed for 1 in D 2 O that arises at 24.6 ppm, which is the expected region for a tertiary amine. 94 When the phosphorus atom is functionalized, the 15 N resonance of the PTA suffers inductive deshielding, as seen for 2 and 3. Upon methylation of the phosphorus atom, compound 2 is obtained, which displays a singlet at 42.9 ppm, while oxidation of the phosphorus, which gives 3, shifts the signal to 64.3 ppm.
Simple protonation of 1 affords compound 4 that displays a singlet due to fast proton exchange. This peak is shifted by only 0.1 ppm in D 2 O with respect to 1, which is the usual behavior for sp 3 nitrogens. 95 Nevertheless, this fact indicates the large difference in the chemical shift between the phosphorus in 31 P NMR, which is approximately 1 order of magnitude larger. 96 Methylation of one of the nitrogen atoms of 1 affords the ligand mPTA (5), which displays the δ 15 N signal corresponding to quaternary nitrogen N 1 that moved by only 0.2 ppm to a higher field with respect to 1. On the contrary, the tertiary nitrogens N 2 suffer a dramatic inductive effect, arising at 34.8 ppm in D 2 O. Therefore, the nonsubstituted PTA nitrogen atoms in 5 are shifted by almost +10 ppm with respect to 1 but −9 ppm with respect to P-methylated regioisomer 2. These results show that the functionalization of the PTA at the phosphorus atom leads to a Δδ 15 N much more pronounced than that at the nitrogen. Further N methylation of 5 gives rise to N,N′-dimethylated derivative 6, usually known as dmPTA, whose CH 3 N 1 -and N 2 -δ 15 N are found at 41.2 and 47.1 ppm, respectively, in acetone-d 6 , showing how these atoms are markedly deshielded by the second methylation. The Δδ 15 N 1 and Δδ 15 N 2 between 6 and 5 are larger (Δδ 15 N 1 = +18.1 ppm, and Δδ 15 N 2 = +12.9 ppm) than those between 5 and 1, due to the inductive effect produced by the quaternary nitrogen atoms, which is doubled in 6 and reciprocally exercised by both N 1 . It is interesting to point out that the mono-and dimethylation of 1 produce a similar effect on the δ 31 P chemical shift.
Derivatives obtained by functionalization of PTA at the two nitrogen atoms suffer, under the appropriate conditions, the  Inorganic Chemistry pubs.acs.org/IC Article lysis of the CH 2 group bridging the functionalized nitrogens. 97 The simplest example may be compound 6, which loses the methylene between the CH 3 N atoms, giving the neutral compound 7, where the δ 15 N 1 and δ 15 N 2 in D 2 O are found at a higher field concerning 6 and also 1 (δ 15 N 1 = 33.1 ppm; δ 15 N 2 40.6 ppm). The difference of ∼10 ppm between the signals of 1 and 7 could be caused by the opening of the adamantane-like cage. A similar shielding effect on the nonfunctionalized atom N 2 is observed also for ligand 8, usually known as DAPTA. For 8, the δ 15 N 2 arises at 31 ppm in DMSO-d 6 , while the acylated nitrogen atoms are found at 107.9−109.1 ppm, in the expected region for amides. 98 It is important to evidence that the solvent polarity also has a slight influence on the chemical shift of the N atoms of the studied compounds. In terms of 2, the 15 N signal is linearly shielded with a decrease in solvent polarity, while compound 1 displays a different behavior: it suffers shielding when the more polar DMSO-d 6 rather than acetone-d 6 is used, but in D 2 O, the signal is deshielded by 0.5 ppm concerning acetone-d 6 . This behavior, which is shown also by 5, can be tentatively addressed considering the possible involvement of the phosphorus atom in hydrogen bonding, which could induce the deshielding of the N PTA atoms in a manner similar to but less intense than that caused by the methylation of the P PTA atom.
δ 15 N of Metal Complexes Containing Ligands 1, 4, and 5. The 1 H− 15 N HMBC of complex [RuClCp(PTA) 2 ] (9), which contains two equivalent PTA ligands, is characterized by a correlation at 40.2 ppm in D 2 O that is relative to its six equivalent nitrogen atoms, together with another set of cross-peaks at 39.3 ppm. This additional signal can be assigned to complex [RuCp(PTA) 2 (D 2 O)] + (10) that is in equilibrium with 9 in water. 99 The δ 15 N 1 of 11 was determined to be shifted by 3.5 ppm to 9 ( Figure 9). As observed in 4, only one 15 N resonance is observed, due to fast proton exchange.
A new step in complexity is represented by diruthenium complex 12, which was synthesized by the reaction of 9 with a half-equivalent of KCN. 79 The 15 N resonances for 12 arise in the same chemical shift range as 9. Additionally, two singlets are observed at 40.8 and 41.8 ppm corresponding with N 1 and N 2 atoms, respectively (see Figure 9), which are due to the asymmetry of the cyanide bridge making the {RuCp(PTA) 2 } + moieties inequivalent. N 1 corresponds to the nitrogen atoms of the PTA bonded to the Ru-CN fragment, and N 2 to those of the PTA bonded to the Ru-NC.
The coordination of one {ZnCl 3 } − moiety or two {ZnCl 2 (H 2 O)} moieties to the nitrogen atoms of 12 leads to trimetallic complex 13 and tetrametallic complex 14, respectively. The absence of multiplicity in their 31  Under adequate reaction conditions, polymeric complexes such as 15 can be obtained from 12, in which two PTA-N atoms are coordinated to two different {CdCl 3 } − units. The 1 H− 15 N HMBC of this polymer provides identical correlations with respect to 12−14, supporting previous evidence that indicates that upon dissolution in water the Cd−N bonds are cleaved. 50 Finally, complex 16, which contains the methylated ligand mPTA (5), shows the resonances relative to methylated atom N 1 and nonmethylated N 2 in DMSO-d 6 , arising at 37.7 and 44.7 ppm, respectively. The differences in the chemical shift between the coordinated and free ligand (Δδ 15 N 1 = +14.6 ppm, and Δδ 15 N 2 = +10.9 ppm) are in the range found for the complexes containing 1. Also, it is interesting to point out that N 1 resonates at a frequency similar to that of the protonated species 11.
In general, the 15 N resonances for complexes 9−16 (Table  S2) and compound 2 appear in a very narrow chemical shift range, suggesting that P methylation of the PTA and the κPcoordination to the ruthenium produce a similar deshielding effect.   (Table S3). Also, N 2 is slightly shielded and resonates at 42.1 ppm. Surprisingly, after coordination to the Ru center, the δ 15 N values of 7 do not vary as much as observed for ligands 1 and 5.
Ligand 7 can coordinate a variety of metallic centers through its methylated nitrogen atoms, affording bimetallic complexes whose antiproliferative activity is usually much higher than those of the monometallic parent compounds and cisplatin. 19,[47][48][49]100 This is the case for complex [RuCp(PPh 3 ) 2 -μ-dmoPTA-1κP:2κ 2 N,N′-ZnCl 2 ](CF 3 SO 3 ) (19), which is 5 times more potent than 18 and 425 times more potent than cisplatin on WiDr colon cancer cells. The chelation of the {ZnCl 2 } moiety closes the bottom rim of the dmoPTA ligand and deshields both N 1 and N 2 , which in CDCl 3 appear at 41.1 and 47.8 ppm, respectively, near the observed signals for 6 in acetone-d 6 . The trend shown by the δ 15 N values of compounds 17−19 is revealed to be very significant to assess the coordination of a second metallic unit to CH 3 N dmoPTA . The Δδ 31 P of the singlets found for 17 and 19 is only 1.2 ppm, while the δ 15 N of their methylated nitrogen differs by 4.21 ppm, making it easier to distinguish whether dmoPTA is protonated or coordinated to a metal.
Complexes 20−22 (Figure 11) contain the ligand PPh 3 and the neutral or protonated PTA and dmoPTA, providing an ideal platform for studying the effect of selective protonation on the δ 15 N of metal complexes containing these aminophosphines. The synthesis of these complexes starts from  (Table S4). The nitrogen atom (N 3 ) of the PTA appears at 41.9 ppm ( Figure  11), which is close to those obtained for complexes 9, 10, and 12 in D 2 O. Complex 20 is susceptible to additional protonation on the PTA, but its HdmoPTA can be deprotonated into dmoPTA. The complex containing the protonated PTA ligand (21) was obtained by the addition of 1 equiv of CF 3 SO 3 H to a solution of 20 in CD 3 OD. The 1 H− 15 N HMBC spectrum of the resulting complex shows how the protonation shifts the 31 P multiplet corresponding to PTA to −27.09 ppm (Δδ 31 P = +12.3 ppm) and shields the N 3 resonance by a magnitude similar to ∼31.9 ppm (Δδ 15 N 3 = −10.0 ppm) with regard to 20. Also, the two 15 N signals corresponding to HdmoPTA appear at higher fields than in 20: that for δ 15 N 1 at 41.5 ppm and that for δ 15 N 2 at 44.1 ppm. Complete deprotonation of 20 employing t BuOK affords complex 22 that shows a slight deshielding of N 3 to 42.7 ppm, while dmoPTA-N 1 and N 2 appear at 31.7 and 39.7 ppm, respectively, being shielded with respect to the corresponding signals in both 20 and 21, which follow the observed trend for 17 and 18, respectively.